Cellular damage during stroke occurs via multiple and diverse pathways. There are considerable data implicating the pathways of secondary inflammation, enhanced matrix metalloproteinase activity, excitotoxicity, apoptosis, free radical injury, and microglial activation. An "ideal" neuroprotectant should favorably influence multiple pathways, should be safe and well tolerated, and should have a long therapeutic time window. Asiatic acid is a plant-derived compound that has been shown to favorably influence multiple deleterious pathways that are activated in stroke through its anti- glutamate, anti-oxidant and anti-inflammatory properties. Our preliminary studies in mice subjected to permanent focal cerebral ischemia suggest that pre-treatment and post-treatment with asiatic acid significantly reduces infarct size without any obvious toxic side effects. Based on this and other published data, asiatic acid could emerge as a candidate for testing as a stroke therapy. However, before clinical testing can take place, rigorous and extensive preclinical pharmacokinetic, safety and efficacy data is required. These data are not available at this time. The goal of this proposal is to generate preclinical pharmacokinetic, efficacy and safety data for the use of asiatic acid as a neuroprotective therapy in stroke. These data will be used to plan more detailed preclinical studies that will allow translation to human testing. PUBLIC HEALTH RELEVANCE: Stroke is one of the leading causes of death and disability in the United States. The only approved FDA therapy must be administered within three hours of symptom onset but most stroke victims are not eligible for this treatment because they arrive in hospital too late. The goal of this project is to evaluate pre-clinically, a safe, innovative and promising natural drug called asiatic acid, because it has produced excellent results in early preclinical stroke studies and has the potential to benefit many more stroke patients.